The discovery of leptin in 1994 revolutionized our knowledge of the role of adipose tissue in nutrition. This hormone is synthesized in adipocytes, and the cell membrane of most cells bears leptin receptors, but it exerts its action mainly in the hypothalamus by inhibiting the production of neuropeptide Y and diminishing appetite. Free and bound leptin is present in plasma, where it has a soluble receptor: sOb-R. The proportion of bound leptin varies during the lifetime according to the amount of fat in the body: the more fat, the higher the production of free leptin. The active form is considered to be free leptin, because it is able to cross the blood-brain barrier (BBB) and is the form found in the cerebrospinal fluid (CSF). Moreover, the direct injection of leptin in the hypothalamus effectively inhibits appetite and increases thermogenesis. Leptin acts in the cell via interactions with its membrane receptor. Seven isoforms of this receptor have been identified, the short (Ob-Ra) and long (Ob-Rb) forms being the best known. Ob-Ra is the membrane carrier for free leptin across the BBB from the plasma to the CSF. Although this receptor is present in many tissues, the highest concentrations are found in the choroid plexus and especially in the arcuate nucleus. Furthermore, a small proportion of plasma free leptin also reaches the brain by passive diffusion. Once it reaches the CSF, leptin binds to the Ob-Rb receptor in the neuronal membrane. This molecule is then phosphorylated by protein-kinase JAK2 in the cytosol, and the leptin-receptor complex interacts with STAT3 to inhibit peptide Y and reduce energy intake. In the periphery, leptin stimulates the oxidation of fat stores in adipocytes and other cells by means of peroxisome proliferator-activated receptor (PPAR) -alpha, subsequently reducing the lipotoxicity in cells that are not designed to store excess lipids. In addition, leptin has been found to interfere in insulin metabolism, cellular growth, placental tropism, reproduction, and immunity. In lean individuals the ratio of free to bound plasma leptin is 1:1. However, in obese persons this equilibrium is altered and the free/bound ratio can be as high as 25:1. The paradoxical finding that obese people have elevated concentrations of free leptin (an active anorexigenic) can be explained by the existence of resistance to leptin transport across the BBB. It has been shown that hypertriglyceridemia is an important cause of this resistance. The well known existence of hypertriglyceridemia in starvation has been interpreted as a natural mechanism to block the access of leptin to the CSF, which keeps the person hungry and seeking food. During the 20th century, however, a new phenomenon appeared: overnutrition and a sedentary lifestyle in large population groups. As a consequence we now confront widespread hypertriglyceridemia, for which natural evolution has not had the time to create an adaptive mechanism. Humans have fallen into a vicious circle of overfeeding with low access of leptin to the hypothalamus, and as a consequence obesity has reached the dimensions of a global epidemic. A therapeutic solution focused on leptin transport could lessen the severity of obesity in many persons. However, before we can focus on this goal, we need to identify the specific site of triglyceride-induced resistance, and then search for agonistic drugs that can act at this site. Nevertheless, to control the epidemic we also need measures to reduce the amount of fat in our diet.